Journal
ONCOTARGET
Volume 7, Issue 33, Pages 53153-53164Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.10625
Keywords
RAS; WSTF; NRG3; paracrine signaling
Categories
Funding
- National Natural Science Foundation of China [81302324]
- Doctoral Research Project of North China University of Science and Technology
- Education Reform Project of North China University of Science and Technology [Q13108-13]
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It remains unclear how the signals of mutant KRAS(G12) in the transformed cells spread to the surrounding non-mutated cells and changes the microenvironment to promote tumor formation. We identified that Williams-Beuren syndrome transcription factor (WSTF), a non-secretory protein, was released in complex with secretory protein-neuregulin-3 (NRG3). The KRASG12 mutant activates the transcription of NRG3. The WSTF/NRG3 in extracellular space could activate oncogenic pathways in normal colon cells carrying wild type KRAS and endow them with the ability to express NRG3 and release WSTF/NRG3. Extracellular WSTF/NRG3 promotes the formation of colon tumors. Blockade of extracellular WSTF could restore cetuximab sensitivity of colon cancer cells with mutant KRAS. The appearance of WSTF/NRG3 in serum and urine correlates with a colon tumor carrying a KRASG12 mutant. In summary, our demonstration provides a new pathway to our understanding of the biological development of complex diseases.
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